The signaling driven by hepatocyte growth factor/scatter factor (HGF/SF) and its receptor tyrosine kinase Met is an important target for therapeutic intervention. HGF/SF (also further abbreviated “HGF”) is a multipotent growth factor that, through activation of its receptor Met, can induce many biological activities including proliferation, transformation, invasion and angiogenesis (Birchmeier et al. (2003) Nat Rev Mol Cell Biol 4: 915-925; Trusolino et al. (2002) Nat Rev Canc 4:289-300). Human and murine HGF are referred to herein as hHGF and mHGF, respectively. Human Met is also referred to as “hMet”. Cells expressing Met are referred to herein as Met+ or hMet+ cells. Compelling evidence demonstrates that HGF/SF-Met signaling plays an important role in tumor development and, particularly, in the onset of invasion and metastatic process (Birchmeier et al., supra). Aberrant expression of Met and/or its ligand have been identified in almost all types of solid tumors derived from tissues of many different origins, and are correlated with poor prognosis. In addition, germline and/or somatic mutations of the Met receptor have been identified in several tumor types.
The growing list of agents with therapeutic potential targeting the HGF-Met pathway include:    (a) neutralizing antibody against human HGF/SF (Cao, B et al., Proc. Natl. Acad. Sci. 98:7443-7448:2001);    (b) NK4, an antagonist of HGF/SF (Date, K. et al., Oncogene17:3045-54, 1998);    (c) ribozymes targeting HGF and Met (Abounader, R et al., FASEB J 16:108-10, 2002);    (d) other small molecule drugs (Webb, C P et al., Cancer Res 60:342-49, 2000; Atabey, N et al., J Biol Chem 276:14308-14, 2001; Christensen, J G et al., Cancer Res. 63:7345-55 2003)
Immune-compromised “host” animals that support the growth of foreign cells and permit tissue xenografts have been used as preclinical models for testing drugs in addition to their utility for studying the biology of tumors in vivo (Mueller et al., 1991) Cancer Metas Rev 3:193-200; Kerbel (2003) Cancer Biol Ther 4 Suppl. 1: S134-39). However, the known animal “systems” are less than satisfactory because they are heterologous (or xenogeneic) to the tumors: implanted human tumor cells with human receptors are acted upon by mouse ligands (e.g., growth factors). These incompatibilities can lead to inappropriate selection of cells with a particular genotype that is manifest as an altered phenotype (compared to the same cell growing in a homologous environment). The importance of matching “donor” cells and tissues to the host is widely established in organ transplantation.
Growth of tissue xenografts in heterologous animal hosts can be significantly altered if, for example, the binding of host ligands with the donor cellular receptor are not of the appropriate high affinity. Thus far, most reagents targeting the HGF-Met pathway have been tested in athymic nude mice which can only provide the murine HGF ligand to the Met receptors of human tumor xenografts. Murine NIH3T3 cells can be transformed and become tumorigenic by ectopic expression of mouse Met but not of hMet (Rong, S et al., Mol Cell Biol 12:5152-58, 1992), which suggests that mouse HGF/SF might have low affinity for human Met receptors.
Transgenic (Tg) animals carry a gene which has been introduced into the germline of the animal, or an ancestor of the animal, at an early (usually one-cell) developmental stage. Many heterologous genes, including ones fused to murine or heterologous promoters, have been introduced into mice as transgenes. See, for example: Wagner, T. et al. (1981) Proc Nat'l Acad. Sci USA 78:5016; Stewart, T A et al. (1982) Science 217:1046; Constantini et al. (1981) Nature 294 92; Lacy et al. (1983) Cell 34:343; McKnight et al. (1983) Cell 34: 335; Brinster et al. (1983) Nature 306:332; Palmiter, R et al. (1982) Nature 300: 611; Palmiter et al. (1982) Cell 29: 701; Palmiter et al. (1983) Science 222:809; Leder, P. et al., U.S. Pat. No. 5,925,803; L. Hansson et al., U.S. Pat. No. 6,222,094
U.S. Pat. No. 6,107,540 (Sawyer, C L et al.), discloses an immune deficient mouse in which human prostate xenografts of locally advanced or metastatic prostate cancer are grown.
U.S. Pat. No. 5,643,551 (Namikawa, R. et al.,) discloses a method for initiating metastasis of human tumor cells under experimental conditions. Immunocompromised non-human mammals implanted with viable xenogeneic organ or tissue material are used as hosts for human tumor cells. The tumor cells are introduced into the chimeric animal after the solid tissue has been implanted and are then able to grow and metastasize as they would in situ. Therapeutic regimens may be evaluated in this system to determine efficacy against metastatic processes.
U.S. Pat. No. 5,530,179 (Terhorst C et al.), discloses a Tg mouse having a substantial deficiency in functionally active natural killer and T lymphocytes which is useful as a model system for immune diseases, tumorigenesis and transplant rejection.
U.S. Pat. No. 6,323,390 (Wu X-R et al.) discloses a Tg mouse containing an oncogene or a tumor suppressor gene operably linked to a urothelium-specific promoter in its germ cells and somatic cells as an animal model system for human bladder cancer.
U.S. Pat. No. 5,602,309 (Albers, K M et al.) discloses Tg mice that express increased levels of nerve growth factor (NGF) in the epidermis and other stratified, keratinized epithelium and that are useful in the study of neurodegenerative disorders of the brain such as Parkinson's disease and Alzheimer's disease and for testing for drug candidates for treating these diseases.
Ectopic in vivo expression of ligand transgenes in host animals can be used to influence the growth of xenografts (Bock, T A et al., J Exp Med 182:2037-43, 1995.). Investigators have described a Tg mouse model in which a murine HGF/SF transgene was ectopically overexpressed, leading to a dramatic increase liver size, enhanced liver regeneration and increased liver tumor formation (Sakata, H et al., Cell Growth Differ 7:1513-23, 1996).
There remains, however, a well-recognized need in the art for an animal model wherein the animals express a foreign, generally xenogeneic, ligand or growth factor which is genetically compatible with xenogeneic cells that are to be grown in that animal. The present inventors have accomplished this for one very important system, and describe herein ectopic expression of “hHGF” (a ligand) in a severe combined-immunodeficient (scid) mouse and the ability of this protein to enhance the growth of known human tumor cell lines that express Met, the receptor for hHGF.